Decoding the spatiotemporal development of the blood-brain barrier in human cortex

Area of Science:

• Neuroscience
• Developmental Biology
• Genetics

Background:

• The blood-brain barrier (BBB) is crucial for central nervous system homeostasis.
• Human BBB formation processes are not well understood.

Purpose of the Study:

• Investigate human BBB development from 6 to 21 gestational weeks (GWs).
• Identify molecular mechanisms and signaling pathways involved in human BBB ontogeny.
• Determine the onset of the human BBB-like transcriptional signature.

Main Methods:

• Single-cell spatiotemporal transcriptomics was employed.
• Analysis spanned human development from 6 to 21 GWs.
• Investigated cell-cell communication and gene regulation.

Main Results:

• Widespread expression of BBB-specific transporters was observed in brain endothelial cells (ECs).
• The human BBB-like transcriptional signature initiates at GW8.
• Neural cells induce BBB transporter expression via CADHERIN-2 (CDH2).
• Neural progenitor cells promote mural cell proliferation.
• Conserved BBB development between humans and mice was revealed.
• H2A.Z.1 was identified as a regulator of angiogenesis and BBB development.

Conclusions:

• This study elucidates key stages and molecular drivers of human BBB development.
• Findings provide insights into BBB ontogeny and potential therapeutic targets for BBB-related disorders.
• CADHERIN-2 and H2A.Z.1 are critical factors in BBB formation.